Peptidases are a class of enzymes (E) which act upon a substrate to cleave an amide linkage (—NH—C(═O)—) to give amino (—NH2) and carboxylic acid (—C(═O)OH) products. 
One peptidase of particular interest is carboxypeptidase G2 (referred to herein as “CPG2”). A preferred substrate for this enzyme is an L-glutamic acid group, inked to an aromatic ring via an amidic, carbamic, or ureidic linkage. 
However, glutamic acid analogs are also acceptable substrates. For example, L-glutamic acid modified at the γ-carbon (e.g., with an amide, —CONH2, instead of an acid, —COOH) also serves as a suitable substrate for CPG2.
CPG2 is also tolerant as to whether the amide group is naked, or is part of a larger linkage, for example, a carbamate or a urea linkage. 
For these compounds, CPG2 yields CO2, L-glutamic acid, and R—ZH, wherein when Z is —O— (carbamates), R—ZH is a hydroxyl compound, R—OH, and when Z is —NH— (ureas), R—ZH is an amino compound, R—NH2, where R is preferably an aromatic group. 
CPG2 and such substrates are useful in enzyme prodrug therapy (EPT) in which CPG2 may act upon a prodrug to yield an active compound. Examples of such therapies include antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), ligand directed enzyme prodrug therapy (LIDEPT), and bacteria directed enzyme prodrug therapy (BDEPT). See, for example, Burke, P. J., et al., 1994; Springer, C. J., et al., 1995; Blakey, D. C., et al., 1996; Springer, C. J., et al., 1996; Emery, S. C., et al., 1998.
In one class of therapy, CPG2 acts upon a prodrug to yield a phenolic nitrogen mustard compound which is useful, for example, in the treatment of a proliferative condition, for example, cancer. 
One method for the synthesis of such prodrug compounds is described in Burke, P. J., et al., 1994. An improved method was subsequently described in Heaton, D. W., et al., 1996 (see FIG. 2  therein) and is shown below: 
This method suffers numerous disadvantages including several difficult and low yield reaction steps, such as:                (a) Step (I): 4-nitrophenyl chloroformate coupling (77% with respect to glutamic acid),        (b) Step (III): reduction of nitroderivative to amine (58%); and,        (c) Step (IV): hydroxyethylation, which is generally a difficult and low yield reaction (49%).        
The present invention relates to new methods for the synthesis of such prodrug compounds, such as N-{4-[N,N-bis(2-haloethylamino)-phenoxycarbonyl}-L-glutamic acid. These new methods have one or more of the following advantages:                (1) higher yield of the desired prodrug with respect to the reagent, glutamic acid, than has been obtained in previous methods.        (2) higher yield of the glutamate conjugation reaction with respect to the precursors (e.g., 5+15 to give 6; 5A+15A to give 6A) than has been obtained in the corresponding conjugation reaction of previous methods (e.g., Step (I) above).        (3) amine substitution (e.g., 1 to 2; 1A to 2A) is performed earlier and with a cheaper reagent (e.g., 4-benzyloxyaniline, 1A) than in previous methods (e.g., the more expensive and advanced intermediate di-t-butyl, N-(4-amino-phenoxycarbonyl)-L-glutamate, in Step (IV) above).        (4) higher yield of amine substitution (e.g., 1 to 2; 1A to 2A) than has been obtained in the corresponding step in previous methods (e.g., Step (IV) above).        (5) simplified work-up of the product of amine substitution (e.g., 1 to 2; 1A to 2A) with respect to that in previous methods (e.g., Step (IV) above).        (6) introduction of the glutamic acid/glutamate residue at a later step (e.g., 5+15 to give 6; 5A+15A to give 6A) than in previous methods (e.g., Step (I) above), and thereby improving the economy of the overall process, in regard to this reagent.        